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Delta9-tetrahydrocannabinol protects hippocampal neurons from excitotoxicity.
Brain Res 2007; 1128(1):61-9BR

Abstract

Excitotoxic neuronal death underlies many neurodegenerative disorders. Because cannabinoid receptor agonists act presynaptically to inhibit glutamate release, we examined the effects of Win 55212-2, a full agonist at CB(1) receptors, and Delta(9)-tetrahydrocannabinol (THC), a partial agonist, on the survival of neurons exposed to an excitotoxic pattern of synaptic activity. Reducing the extracellular Mg(2+) concentration ([Mg(2+)](o)) to 0.1 mM evoked an aberrant pattern of glutamatergic activity that produced synaptically mediated death of rat hippocampal neurons in culture. Neuronal viability was quantified with a multiwell fluorescence plate scanner equipped to detect propidium iodide fluorescence. Win 55212-2 (100 nM) and THC (100 nM) significantly reduced 0.1 mM [Mg(2+)](o)-induced cell death by 77 +/- 11% and 84 +/- 8%, respectively. Interestingly, the protection afforded by THC was not significantly different from that produced by Win 55212-2, suggesting that attenuation without a complete block of excitatory activity is sufficient for neuroprotection. The effect of prolonged drug exposure on the neuroprotection afforded by cannabinoid receptor agonists was also studied. When cultures were pretreated for 24 h with Win 55212-2 (100 nM) or THC (100 nM), inhibition of 0.1 mM [Mg(2+)](o)-induced toxicity was significantly reduced to 39 +/- 19% and 45 +/- 13%, respectively. Thus, desensitization of CB(1) receptors diminishes the neuroprotective effects of cannabinoids. This study demonstrates the importance of agonist efficacy and the duration of treatment on the neuroprotective effects of cannabinoids. It will be important to consider these effects on neuronal survival when evaluating pharmacologic treatments that modulate the endocannabinoid system.

Authors+Show Affiliations

Department of Pharmacology, University of Minnesota, 6-120 Jackson Hall, 321 Church Street SE, Minneapolis, MN 55455-0217, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

17140550

Citation

Gilbert, Glenna L., et al. "Delta9-tetrahydrocannabinol Protects Hippocampal Neurons From Excitotoxicity." Brain Research, vol. 1128, no. 1, 2007, pp. 61-9.
Gilbert GL, Kim HJ, Waataja JJ, et al. Delta9-tetrahydrocannabinol protects hippocampal neurons from excitotoxicity. Brain Res. 2007;1128(1):61-9.
Gilbert, G. L., Kim, H. J., Waataja, J. J., & Thayer, S. A. (2007). Delta9-tetrahydrocannabinol protects hippocampal neurons from excitotoxicity. Brain Research, 1128(1), pp. 61-9.
Gilbert GL, et al. Delta9-tetrahydrocannabinol Protects Hippocampal Neurons From Excitotoxicity. Brain Res. 2007 Jan 12;1128(1):61-9. PubMed PMID: 17140550.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Delta9-tetrahydrocannabinol protects hippocampal neurons from excitotoxicity. AU - Gilbert,Glenna L, AU - Kim,Hee Jung, AU - Waataja,Jon J, AU - Thayer,Stanley A, Y1 - 2006/11/30/ PY - 2005/08/16/received PY - 2006/02/28/revised PY - 2006/03/03/accepted PY - 2006/12/5/pubmed PY - 2007/3/28/medline PY - 2006/12/5/entrez SP - 61 EP - 9 JF - Brain research JO - Brain Res. VL - 1128 IS - 1 N2 - Excitotoxic neuronal death underlies many neurodegenerative disorders. Because cannabinoid receptor agonists act presynaptically to inhibit glutamate release, we examined the effects of Win 55212-2, a full agonist at CB(1) receptors, and Delta(9)-tetrahydrocannabinol (THC), a partial agonist, on the survival of neurons exposed to an excitotoxic pattern of synaptic activity. Reducing the extracellular Mg(2+) concentration ([Mg(2+)](o)) to 0.1 mM evoked an aberrant pattern of glutamatergic activity that produced synaptically mediated death of rat hippocampal neurons in culture. Neuronal viability was quantified with a multiwell fluorescence plate scanner equipped to detect propidium iodide fluorescence. Win 55212-2 (100 nM) and THC (100 nM) significantly reduced 0.1 mM [Mg(2+)](o)-induced cell death by 77 +/- 11% and 84 +/- 8%, respectively. Interestingly, the protection afforded by THC was not significantly different from that produced by Win 55212-2, suggesting that attenuation without a complete block of excitatory activity is sufficient for neuroprotection. The effect of prolonged drug exposure on the neuroprotection afforded by cannabinoid receptor agonists was also studied. When cultures were pretreated for 24 h with Win 55212-2 (100 nM) or THC (100 nM), inhibition of 0.1 mM [Mg(2+)](o)-induced toxicity was significantly reduced to 39 +/- 19% and 45 +/- 13%, respectively. Thus, desensitization of CB(1) receptors diminishes the neuroprotective effects of cannabinoids. This study demonstrates the importance of agonist efficacy and the duration of treatment on the neuroprotective effects of cannabinoids. It will be important to consider these effects on neuronal survival when evaluating pharmacologic treatments that modulate the endocannabinoid system. SN - 0006-8993 UR - https://www.unboundmedicine.com/medline/citation/17140550/abstract/Delta_9__Tetrahydrocannabinol_protects_hippocampal_neurons_from_excitotoxicity L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-8993(06)00725-6 DB - PRIME DP - Unbound Medicine ER -